Retroviral-driven overexpression of genes encoding four transcription factors (Oct 3/4, Sox2, Klf4, and c-Myc) is sufficient to generate pluripotent cells from adult fibroblasts. Whether these induced pluripotent stem (iPS) cells arise from preexisting stem cells or from reprogramming of differentiated cells has not been clear. The group that first developed the iPS cell method reports that iPS cells made from adult mouse epithelial cells from the stomach (gastric epithelia) and liver (primary hepatocytes) were very similar to embryonic stem (ES) cells in several respects, including morphology, proliferation rate, pluripotency, and gene expression profile. Lineage tracing experiments revealed that iPS cells generated from primary hepatocytes were derived from cells that expressed the liver marker albumin, illustrating that differentiated cells can indeed be reprogrammed to give rise to iPS cells. Liver-derived iPS cells expressed ES cell markers more robustly than did those derived from adult fibroblasts, and they exhibited more extensive, although not complete, promoter demethylation, suggesting that the epithelial cells were more efficiently reprogrammed than were the fibroblasts. Chimeric mice containing fibroblast-derived iPS cells had a high risk of developing cancer as adults, presumably because the iPS cells contained a retrovirally encoded copy of the oncogene c-Myc. The incidence of cancer was reduced in chimeras containing liver-derived iPS cells. Furthermore, it was possible to generate epithelium-derived iPS cells without retroviral expression of the oncogene c-Myc, a feature that could be used to further limit the propensity of these cells to cause cancer.